Synthesis of β and γ‐fluorenylmethyl esters of respectively Nα‐Boc‐L‐aspartic acid and Nα‐Boc‐L‐glutamic acid

The orthogonal synthesis of N x ‐Boc‐L‐aspartic acid‐γ‐fluorenylmethyl ester and N α ‐Boc‐L‐glutamic acid‐δ‐fluorenylmethyl ester is reported. This is a four‐step synthesis that relies on the selective esterification of the side‐chain carboxyl groups on N x ‐CBZ‐ l ‐aspartic acid and N α ‐CBZ‐ l ‐glutamic acid. Such selectivity is accomplished by initially protecting the a‐carboxyl group through the formation of the corresponding 5‐oxo‐4‐oxazolidinone ring. Following side‐chain esterification, the α‐carboxyl and α‐amino groups are deprotected with acidolysis. Finally, the α‐amino group is reprotected with the t‐butyl‐oxycarbonyl (Boc) group. Thus aspartic acid and glutamic acid have their side‐chain carboxyl groups protected with the base‐labile fluorenylmethyl ester (OFm) and their α‐amino groups protected with the acid‐labile Boc group. These residues, when used in conjunction with N x ‐Boc‐ N ε ‐Fmoc‐ l ‐lysine, are important in the formation of side‐chain to side‐chain cyclizations, via an amide bridge, during solid‐phase peptide synthesis.